Today, the U.S. Food and Drug Administration (FDA) released three draft guidance documents designed to assist industry in developing biosimilars. Biosimilar products are biological products shown to be highly similar (biosimilar) to biological products previously approved by FDA (known as reference products). Section 351(k) of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), signed into law in March 2010 as part of the Patient Protection and Affordable Care Act, established an abbreviated approval pathway for biosimilar products. Applications to FDA seeking approval of biosimilar products are known as 351(k) applications.
The draft guidances, which have been eagerly anticipated by biosimilars stakeholders for some time, address both scientific and quality considerations for demonstrating biosimilarity to reference products and also provide information about implementation of the BPCI Act in a Q&A format. Each guidance is briefly summarized below.
Guidance for Industry: Scientific Considerations in
Demonstrating Biosimilarity to a Reference Product (Scientific
Guidance)
According to the Scientific Guidance, "FDA
intends to consider the totality of the evidence provided by a
sponsor to support a demonstration of biosimilarity, and recommends
that sponsors use a stepwise approach in their development of
biosimilar products." (Scientific Guidance at 2.) The Guidance
first acknowledges the unique complexities of protein products, and
addresses the resulting scientific and manufacturing process
considerations. The Guidance then outlines the stepwise approach to
demonstrating biosimilarity and explains how FDA will use the
totality of the evidence approach to assess that demonstration.
The Guidance also includes a detailed discussion of the data and information needed to support a demonstration of biosimilarity, including guidance relating to (i) structural analysis, (ii) functional assays, (iii) animal data, and (iv) clinical studies. The guidance concludes by briefly discussing postmarketing safety monitoring considerations and consultation with FDA.
Guidance for Industry: Quality Considerations in
Demonstrating Biosimilarity to a Reference Protein Product (Quality
Guidance)
The Quality Guidance "focuses on therapeutic
protein products and provides an overview of analytical factors to
consider in demonstrating biosimilarity between a proposed protein
product and the reference product." (Quality Guidance at 1.)
After first setting forth general principles regarding the
importance of performing a robust characterization of the proposed
biosimilar product as part of an analytical comparison of the
proposed product and the reference product, the Guidance identifies
and explains nine factors for consideration in assessing whether
the products are highly similar: (1) expression system, (2)
manufacturing process, (3) assessment of physiochemical properties,
(4) functional activities, (5) receptor binding and immunochemical
properties, (6) impurities, (7) reference product and reference
standards, (8) finished drug product, and (9) stability. The
Guidance also lists twenty-one "relevant guidances" for
potential consideration during biosimilar product development.
Guidance for Industry: Biosimilars: Questions and
Answers Regarding Implementation of the Biologics Price Competition
and Innovation Act of 2009 (Q&A Guidance)
The Q&A Guidance "provides answers to
common questions from sponsors interested in developing proposed
biosimilar products, biologics license application (BLA) holders,
and other interested parties" regarding FDA's
interpretation of the BPCI Act. (Q&A Guidance at 1.) The
Q&A Guidance is organized into three sections: (1)
Biosimilarity or Interchangeability; (2) Provisions Related to
Requirements to Submit a BLA for a "Biological Product";
and (3) Exclusivity.
First, the Biosimilarity or Interchangeability section addresses fundamental questions such as whom to contact at FDA with questions about biosimilars development, when to request an initial meeting to discuss a proposed biosimilar development program, and what types of information are needed to support a 351(k) application, including issues relating to differences between proposed products and reference products. Second, the Provisions Related to Requirements to Submit a BLA for a "Biological Product" section provides information on FDA's interpretation of the term "protein (except any chemically synthesized polypeptide)" as used in the definition of "biological product" under the BPCI Act, and also explains when a proposed biological product will be considered to be in the same "product class" as a protein previously approved under section 505 of the Food, Drug, and Cosmetic Act. Third, the Exclusivity section includes information about reference product exclusivity and orphan exclusivity. Finally, the Q&A Guidance states that "FDA intends to update this guidance to include additional Q&A's as appropriate." (Q&A Guidance at 2.)
Conclusion
The issuance of these three draft guidance documents
is an important step in establishing a regulatory process for
bringing biosimilar products to market under the framework
established by the BPCI Act. To further this effort, FDA is seeking
public comment on the draft guidances. Instructions and timing for
submitting comments will be announced in a forthcoming Federal
Register notice. Stakeholders should carefully review the draft
guidances and provide comments to the Agency to make their views
and concerns about the biosimilar product development process known
and begin a productive dialogue. Further, the Q&A Guidance
specifically notes that proposed questions for inclusion in future
updates to the guidance are encouraged. The process for raising
such questions will be described in the upcoming Federal Register
notice.
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